One of the factors which determines the proliferation state of cells is the balance between the growth-promoting effects of proto-oncogenes, and the growth-constraining effects of tumor-suppressor genes.
One mechanism by which these tumor-suppressor genes exert their growth-constraining effect is by inducing the cell to undergo a physiological type of death. Such a controlled cell death is evident in a multitude of physiological conditions including metamorphosis, synaptogenesis of neurons, death of lymphocytes during receptor repertoire selection, controlled homeostasis in the bone-marrow and other proliferative tissues, and others. Such cell death is regulated by the interaction of the cell with other cells or with cell products, for example through the activity of suitable cytokines.
Genetic mutations that inactivate the suppressor genes, liberate the cell from normal growth constraints imposed by other cells or by cytokines, resulting in an uncontrolled growth or viability of the cell without any relation to external signals. This uncontrolled growth is a step in tumorigenesis.
To date, only a few tumor-suppressor genes have been fully characterized including the retinoblastoma (Rb) gene, p53, DCC, NM23 WT-1, NF-1, APC, and ras suppressor genes. A mutation in either of the above genes, probably in both alleles, which leads to either blockage of expression, or production of a faulty protein, hampers the normal control of growth and viability of cells and may thus give rise to cancer.
A number of links have been discovered between programmed cell death and the multi-stage process of tumorigenesis. The first discovery was the finding that the Bcl2 gene, activated by the typical chromosomal translocation in human follicular lymphomas, is a suppressor of cell death (Tsujimoto Y., et al., 1985, Nature 315:340-343). The second link was the finding that p53, the most commonly mutated tumor suppressor gene in various human tumors, functions as a positive mediator of apoptosis. p53 induces cell death in response to different stresses such as gentoxic damage and hypoxia. Thus, the extension of cell viability followed by the accumulation of genetic damage and by the uncontrolled growth of the tumor, are among the mechanisms through which inactivating mutations of p53 promote tumorigenesis (Lowe, S. W., et al., 1993, Nature 362:847-849). More recently it has been reported that the adenomatous polyposis coli (APC) tumor suppressor gene, that is frequently lost or inactivated in early stages of colorectal cancers, induced the death of colorectal cells in culture (Morin et al., 1996, Proc. Natl. Acad. Sci. 93:7950-54), thus providing a third link to apoptotic control. In another study, apoptosis in micrometastases was found to be significantly reduced after induction of angiogenesis as a result of a decrease in levels of circulating angiogenic inhibitors (Holmgren, L., et al. 1995, Nature Medicine 1:149-153). However, very little has been revealed with respect to earlier stages of metastasis such as detachment from the primary tumor, dissemination and invasion processes.
Growth-inhibiting cytokines have a double effect on the target cell. They can either inhibit the proliferation of the cell, and/or give rise to cell death. To date, blockage or activation of expression of known tumor-suppressor genes was shown to counteract or enhance, respectively, cytokines' inhibition of cells' growth (reviewed by A. Kimchi, 1992, J. Cell Biochem., 50:1-9) but did not have any effect on the death promoting action of cytokines. For example, the growth inhibitory response to cytokines such as TGF-.beta., was markedly reduced by the inactivation of the Rb gene, or the response to IL-6 was enhanced by introducing activated p53 genes (Pietenpol et al., 1990, Cell, 61:777-785; Levy et al., 1993, Mol. Cell. Bio., 13:7942-7952).
Thioredoxin, a small hydrogen carrier protein, has previously been implicated in the IFN-.gamma.-mediated growth arrest of HeLa cells (Deiss, L. P. and Kimchi, A. 1991, Science 234:117-120).